tbuckley/cabot-search huggingface dataset:
DIPG-05. EVALUATION OF TELOMERE-MODIFYING COMPOUND THIO AS A RADIOSENSITIZER AND IMMUNOMODULATOR TO TREAT DIPG
Authors: Deepak Mishra, Banlanjo Umaru, Shiva Senthil Kumar, Sergei Gryaznov, Rachid Drissi
Journal: Neuro-Oncology (2023)

Abstract Diffuse intrinsic pontine glioma (DIPG) is one of the most aggressive tumors of the central nervous system in children. Radiotherapy remains the only standard treatment but is rarely curative. In recent years, several immunotherapy strategies have emerged as an option to treat DIPG. However, the low mutational burden and rare infiltration of T lymphocytes, render these tumors immunologically “cold” and therefore pose challenges for general immunotherapy. We have previously reported in pediatric brain tumors the preclinical validation of THIO (6-thio-2’-deoxyguanosine), a telomerase substrate precursor analog. Treatment of cancer cells with THIO caused both telomeric and genomic DNA damage and rapid cell death. In vivo treatment delayed tumor growth in mouse models of high-risk medulloblastoma and DIPG. Importantly, THIO crosses the blood-brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. The cGAS-STING pathway is a cellular mechanism that senses cytosolic double stranded DNA, stimulating type I interferons (IFNs) and IFN-stimulated genes, thereby activating the innate and adaptive anti-tumor immune responses. Micronuclei resulting from cell division in the presence of unresolved DNA damage, has been shown to be recognized by the cGAS-STING pathway. THIO was shown to induce anti-tumor immunity through micronuclei formation in colon and lung tumor models. We hypothesized that THIO treatment will activate anti-tumor immunity in DIPG. Our results indicate that THIO treatment sensitized DIPG cells to ionizing radiation (IR) leading to a significant decrease in DIPG cell proliferation. We are currently testing this combination in vivo in an orthotopic mouse model of DIPG. We will present results on the potential of THIO to activate anti-tumor immunity through the activation of Sting pathway in a syngeneic mouse model of DIPG. These preclinical studies will support potential use of THIO in combination with IR to treat children with high-risk pediatric brain tumors.
OTHR-10. COLLABORATIVE EFFORTS FOR HOSPITAL-BASED BIOBANK DEVELOPMENT AND OPTIMIZATION TO ENSURE QUALITY PEDIATRIC SPECIMENS FOR TRANSLATIONAL RESEARCH
Authors: Brittany Lebert, Maxine Gonzalez-Vega, Samer Elbabaa, Julia Hegert, Avery Wright, Ana Aguilar-Bonilla, Amy Smith
Journal: Neuro-Oncology (2023)

Abstract In recent years, drastic improvements in sequencing technologies have led to a better understanding of the specific genetic drivers of cancer. However, one of the greatest barriers to these discoveries is access to primary patient tumor tissue, especially in cancers of the Central Nervous System (CNS). In many cases tissue from surgery is processed and stored in Formalin-Fixed Paraffin-Embedded (FFPE) blocks, which sets limitations on downstream applications. In 2015, our team launched an initiative to collect and efficiently store samples from pediatric CNS tumor patients during surgeries and autopsies. Through extensive collaboration between Neuro-Oncology, Neurosurgery, Pathology, and our Translational Laboratory, we have optimized the collection process to effectively preserve sample integrity and therefore maximize their potential usage. To date, we have collected over 4,509 samples from 293 patients (636 flash-frozen tissue, 1,026 plasma &amp; buffy coat, 748 serum, 996 whole blood, 316 Cerebrospinal Fluid (CSF), and 787 parental blood samples). In addition, we have cultured 31 primary cell lines and collected over 242 dissociated tumor specimens for implantation into patient-derived xenograft (PDX) mouse models. Through our partnership with neurosurgery and pathology, we are permitted to attend surgeries and autopsies to immediately flash-freeze tumor tissue in liquid nitrogen, typically within minutes of the tissue being removed from the body. This immediate flash-freezing process aims to ensure specimen integrity and preserve molecular profiles. From there, the tissue is either stored in our -140oC freezer for future use or sent to partnered consortiums, including the Children’s Brain Tumor Network (CBTN) and Gift from a Child. Since the optimization of the collection process, the focus has now shifted to investigating the efficacy of our storage methods by quantifying DNA/RNA integrity over time. By ensuring the successful preservation of the samples, we can maximize their impact in the pediatric neuro-oncology research field.
ATRT-09. COMBINATION OF THE PI3K INHIBITOR PAXALISIB WITH THE NUCLEOSIDE ANALOG GEMCITABINE ACTIVATES THE INTEGRATED STRESS RESPONSE AND EXTENDS SURVIVAL IN ORTHOTOPIC MODELS OF ATYPICAL TERATOID/RHABDOID TUMORS
Authors: Tyler Findlay, Kristen Malebranche, Anupa Geethadevi, Charles Eberhart, Eric Raabe, Jeffrey Rubens
Journal: Neuro-Oncology (2023)

Abstract Relapsed atypical teratoid/rhabdoid tumors (AT/RT) are a deadly disease without a known cure. The Pacific Pediatric Neuro-Oncology Consortium (PNOC) is looking for effective combination therapies for an upcoming clinical trial to better treat relapsed AT/RT. We have previously identified that AT/RT are dependent on activation of mTORC1 and mTORC2 for growth and survival. Paxalisib is a highly brain penetrant PI3k inhibitor which acts upstream of mTOR to simultaneously inhibit mTORC1/2. In murine orthotopic xenograft models of AT/RT, Paxalisib significantly extends survival as a single agent therapy (CHLA-06: 40 to 54 days, p=0.001; BT12: 21 to 35 days, p=0.02). However, to improve the durability of this single agent therapy, we evaluated the efficacy of rational therapeutic partners. Analysis of RNAseq following mTOR inhibition (mTORi) showed an upregulation of genes associated with the integrated stress response (ISR) (ATF4, CHOP, PPP1R15A; t-test p&amp;lt;0.05). Gemcitabine is a pyrimidine nucleoside prodrug, which inhibits DNA synthesis and induces DNA damage, also leading to ISR activation. While the ISR can be protective, intense or prolonged activation leads to cell death. We therefore hypothesized that Paxalisib would combine with Gemcitabine to over-activate the ISR and drive AT/RT cell death. Through protein analyses, we demonstrate that combination therapy further activates the ISR compared to DMSO control (Western Blot: phospho-eIF2α, ATF4, and CHOP). Combination therapy also increases apoptosis (Western blot cPARP, MUSE Annexin V Assay) and synergizes to decrease AT/RT cell growth (SynergyFinder BLISS score CHLA-06: 16.8, BT12: 14.3, CHLA-266: 13.9). In mice bearing CHLA-06 orthotopic tumors, Paxalisib/Gemcitabine combination therapy slows tumor growth (Bioluminescent imaging) and extends median survival from 22 to 82.5 days (p&amp;lt;0.0001) compared to vehicle control treated mice. We aim to translate these results in this upcoming PNOC clinical trial to treat relapsed AT/RT.
LGG-23. OUTCOMES UTILIZING BRAF INHIBITION MONOTHERAPY IN BRAFV600E MUTATED PEDIATRIC LOW GRADE GLIOMAS
Authors: Sheila McThenia, Kartik Reddy, Adam E Goldman-Yassen, Rachel Gray, Erin Connelly, Brooke Patteson, Dolly Aguilera, Robert Craig Castellino, Jason Ronald Fangusaro, Anna Janss, Claire Mazewski, Tobey MacDonald
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Pediatric low-grade glioma (pLGG) tumorigenesis is driven by activation of the RAS/RAF/MAPK pathway. pLGGs have an overall survival over 95%; however, patients harboring a BRAFV600E alteration may have worse outcomes. Combined BRAF/MEK inhibition following incomplete resection demonstrated improved outcome in pLGG compared to combined carboplatin/vincristine chemotherapy. We evaluated efficacy and tolerability of single agent BRAF inhibitor treatment in our single institution pLGG cohort. METHODS We performed a single institution retrospective analysis, (2013-2023) at Children’s Healthcare of Atlanta on patients 0-21 years old with new or progressive BRAFV600E mutated pLGG, who were treated off-study with BRAF inhibitor monotherapy. We evaluated 2-year Progression Free Survival (PFS) and Objective Response (CR+PR). All toxicities were evaluated and described. RESULTS We identified fifteen patients with BRAFV600E mutated pLGGs treated with BRAF inhibitor monotherapy. Median age of diagnosis: 5.8 years (0.20–18.0). Histologic diagnosis: pilocytic astrocytoma (PA)(N=3); atypical PA (N=1); ganglioglioma (N=3); atypical ganglioglioma (N=3); pleomorphic xanthoastrocytoma (PXA)(N=2); LG neuroepithelial tumor (N=1); infiltrating glioma (N=1); and LGG (NOS)(N=1). Tumor location: hypothalamus/optic chiasm (N=5); third ventricle/thalamus (N=3); parietal/temporal lobe (N=3); brainstem (N=2); and cervicomedullary junction/spinal cord (N=2). Mean therapy duration: 30.7 months (3.9-74.6). Median follow-up: 32.6 months (16-78.1). Two-year PFS: 80% (12/15). Objective Response(OR) for 14 evaluable patients at 1-year on initial BRAF inhibitor therapy: 43% (0/14 CR+6/14 PR). Patients tolerated treatment with Grade 1 rash being the most common toxicity. Three of 15 patients (20%) discontinued therapy due to toxicities, including rashes, arthralgias/myalgias (Grade 2), and one corneal lesion. CONCLUSIONS In our small cohort of incompletely resected BRAFV600E mutated pLGGs, BRAF inhibition monotherapy was effective and well tolerated with an OR comparable to published outcomes of dual MEK/BRAF inhibitor therapy. This promising treatment should be further studied in prospective clinical
METB-12. CLINICAL MONITORING OF MEASURABLE RESIDUAL DISEASE BY CELL-FREE DNA IN PEDIATRIC BRAIN TUMORS
Authors: Erin Crotty, Bonnie Cole, Vera Paulson, Christina Lockwood, Sarah Leary
Journal: Neuro-Oncology (2023)

Abstract Conventional response monitoring relies on imperfect tools like MRI and cerebrospinal fluid (CSF) cytology to detect measurable residual disease (MRD) in children with brain tumors. “Liquid biopsy” techniques provide a minimally-invasive method for MRD detection by identifying fragments of cell-free DNA (cfDNA) shed from tumor cells following cell death. Early detection of MRD has been proposed as a clinically actionable biomarker that may allow clinicians to reliably detect tumor versus treatment effect, intensify therapy prior to relapse, and minimize toxicity. Our center is currently evaluating low-pass whole genome sequencing (LP-WGS) in children with brain tumors receiving standard of care therapy for real-time MRD assessment. Following informed consent, patients are enrolled on the Seattle Children’s Hospital Tissue Banking and Biology Protocol, and CSF samples are collected prospectively by lumbar puncture during routine clinical care. LP-WGS is performed in a CAP/CLIA certified environment with return of results to the referring clinician. In addition to feasibility as a prognostic and predictive biomarker, correlative studies will investigate if neuroinflammatory and immunologic profiles change with the presence of MRD using CNS cytokine signatures, including CXCL-12, CCL-2, MMPs, CD163, and GFAP. Preliminary cfDNA studies of children with embryonal tumors suggest LP-WGS is both a sensitive and clinically valuable test to detect tumor-associated copy number variants (CNVs). Thirty of thirty-one (97%) of CSF samples from 17 patients demonstrated adequate cfDNA for LP-WGS testing. Key CNVs detected included monosomy 6, isodicentric chromosome 17, and amplifications of MYCN and TTYH1. Among 8 samples obtained at initial tumor staging, LP-WGS detected tumor in 7/8 (1 negative ATRT without CNVs), whereas only 2/8 were positive by cytology. Two samples acquired additional chromosomal alterations at progression beyond those observed in the original tumor. Future prospective clinical trials are warranted to determine how MRD will transform clinical care and patient outcomes.
OUTC-01. ESTABLISHING THE PSYCHOMETRIC VALIDITY OF ATTENTIONAL MEASURES APPLIED TO THE PAEDIATRIC NEURO-ONCOLOGY POPULATION: A SYSTEMATIC REVIEW
Authors: Sarah Verity, Alexander Hagan
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND: Associated with hydrocephalus, cranial irradiation, and certain chemotherapeutic agents, impairment in attention is a common feature of childhood brain tumour survivorship. Attentional processes are implicated in a number of cognitive functions, supporting sustained and selective attention, inhibition of competing stimuli, and management of divided attention (multi-tasking). Acquired attentional deficit reported in childhood survivors of brain tumour is correlated with reduced academic attainment, slowed intellectual development, poor peer relationships, and lower overall quality of life. Accurate identification of tumour-related attentional impairment is a prerequisite to access appropriate rehabilitative intervention. Despite this, no attentional measures have been adequately normed on the paediatric brain tumour population. As such, there exists little agreement as to which measure is most suitable for current research or clinical practice. AIM: This prospective study will assess the utility of common measures of childhood attention used in the paediatric Neuro-Oncology population. METHOD: Comprehensive database searches will be conducted to identify relevant articles that address the validity, reliability, and capability of attentional measures currently used within paediatric Neuro-Oncology populations. The psychometric properties and clinical utility of each measure will be reviewed using a purpose-developed evaluative tool. The strengths and limitations of particular measures when applied to this clinical population will be discussed. Recommendations for the utility for and against measures in future research or clinical application will be provided. FINDINGS: Analyses of these data continues with an aim to present initial findings by May 2023.
TRLS-07. GLOBAL POST-MARKETING SURVEILLANCE DATA FROM PEDIATRIC AND ADULT PATIENTS WITH CENTRAL NERVOUS SYSTEM MALIGNANCIES TREATED WITH TUMOR TREATING FIELDS (TTFIELDS) THERAPY BETWEEN 2011–2022
Authors: Maciej M Mrugala, Wenyin Shi, Fabio Iwamoto, Rimas V Lukas, Joshua D Palmer, John H Suh, Martin Glas
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields therapy is approved for adults with recurrent (r) and newly diagnosed (nd) glioblastoma (GBM), based on the phase 3 EF-11 (TTFields 200 kHz) and EF-14 studies (TTFields therapy 200 kHz + temozolomide), respectively, which showed clinical benefit without increase in systemic adverse events (AEs). Pediatric patients were not included in the EF-11 and EF-14 studies. Here, we present pediatric safety data from an updated global post-marketing surveillance (PMS) analysis of patients with brain tumors treated with TTFields therapy, over an 11-year timeframe. METHODS Unsolicited PMS data from patients with brain tumors who received TTFields therapy from October 2011-March 2022 in North America, Europe, Middle East, Africa, and Japan were included. AEs were categorized using MedDRA version 25.1. RESULTS Overall, 25,898 patients were included. Diagnoses were ndGBM (68%), rGBM (26%), anaplastic astrocytoma/oligodendroglioma (4%) and other (2%). Two-thirds of patients were male. The analysis included 93 (0.4%) pediatric/adolescent patients (&amp;lt;18 years). In pediatric patients, 62% experienced ≥1 AE, with 53% related to TTFields therapy; these values were comparable with the overall population (73% and 56%, respectively). The most common treatment-related AEs in pediatric patients were: skin reaction (39%), heat sensation (14%), and headache (12%); and in the overall population were: skin reaction (43%), electric sensation (14%), and heat sensation (12%). CONCLUSIONS This long-term, global, real-world data analysis, including pediatric patients with brain tumors, demonstrates a tolerable safety profile of TTFields therapy, consistent with pivotal clinical studies. There were no major differences in AEs between pediatric and adult patients and no new safety signals identified in the pediatric population. Consistent with the overall dataset, most AEs in pediatric patients were localized mild–moderate skin events, which are typically easily managed.
LGG-17. EPIGENETICALLY DEFINED ANGIOCENTRIC GLIOMAS MAY LACK ANGIOCENTRIC GROWTH AND INSTEAD SHOW A VARIETY OF GROWTH PATTERNS
Authors: Lotte Stegat, Jenny L Rohwer, Damian Stichel, Daniel Schrimpf, Roland Coras, Mélanie Pagès, Arnault Tauziède-Espariat, Pascale Varlet, Volkmar H Hans, Jochen Meyer, Jens Schittenhelm, Ori Staszewski, Edmund Cheesman, Markus Glatzel, Simone Schmid, Pieter Wesseling, Andrey Korshunov, Alexandra Sexton-Oates, Ulrich Schüller, Lenne-Triin Kõrgvee, Sabine Mueller, Adriana Olar, Matija Snuderl, Leonille Schweizer, Eleonora Aronica, Felix Sahm, Andreas von Deimling, Ingmar Blumcke, David T W Jones, David Capper, Annika K Wefers
Journal: Neuro-Oncology (2023)

Abstract Angiocentric glioma mainly occurs in children and young adults. It is associated with a good prognosis (CNS WHO grade 1). Molecularly, most angiocentric gliomas have a MYB-QKI fusion. Histologically, angiocentric gliomas were initially defined by an angiocentric growth of the tumor cells. However, we noticed that epigenetically defined angiocentric gliomas often get different diagnoses based on their histology as they may lack this angiocentric growth pattern. We collected 48 epigenetically defined angiocentric gliomas from 46 patients with sufficient tissue for histological and molecular analyses (DNA methylation analyses; RNA sequencing of a subset; 37 supratentorial and 11 infratentorial cases). The classification was done using unsupervised hierarchical cluster analyses from DNA methylation data and the brain tumor classifiers v11b4 and v12.5 (www.molecularneuropathology.org). Angiocentric gliomas were epigenetically distinct from the diffuse astrocytomas, MYB- or MYBL1-altered. A MYB-QKI fusion was detected in 69% (n = 18/26) of angiocentric gliomas, confirming the diagnosis. Other fusions detected were fusions of MYB with intergenic sites, mainly close to QKI (19%; n = 5/26), and MYBL1-QKI (8%; n = 2/26). We then did a histological workup of these cases. Only 75% showed the typical angiocentric growth pattern that often was not very pronounced. Many angiocentric gliomas displayed an unspecific growth while others resembled pilocytic astrocytoma or ependymoma. Hence, about 59% of angiocentric gliomas were initially misdiagnosed without molecular analyses (supratentorial 50%, infratentorial 100%). We obtained similar results expanding the cohort with further epigenetically defined angiocentric gliomas for which no tissue for a histological re-evaluation was available (total 68 cases; 50 supratentorial, 12 infratentorial; 65 patients). In this expanded cohort, 54% of cases were initially misdiagnosed (45% of supratentorial and 100% of infratentorial cases). In summary, we show that angiocentric glioma often does not show the typical angiocentric growth pattern. Thus, molecular analyses are needed for a reliable diagnosis.
DIPG-20. DELINEATING MEDIATORS OF ONCOGENESIS IN FOXR2-EXPRESSING DIFFUSE MIDLINE GLIOMAS
Authors: Jessica Tsai, Paloma Cejas, Marissa Coppola, Dayle Wang, Smruti Patel, David Wu, Phonepasong Arounleut, Xin Wei, Ningxuan Zhou, Sudeepa Syamala, Frank Dubois, Kristine Pelton, Jayne Vogelzang, Cecilia Sousa, Audrey Baguette, Xiaolong Chen, Alexandra Condurat, Sarah Dixon-Clarke, Kevin Zhou, Sophie Lu, Elizabeth Gonzalez, Madison Chacon, Jeromy Digiacomo, Rushil Kumbhani, Dana Novikov, Maria Tsoli, David Ziegler, Uta Dirksen, Natalie Jager, Gnana Prakash Balsubramanian, Christof Kramm, Michaela Nathrath, Stefan Bielack, Suzanne Baker, Jinghui Zhang, James McFarland, Gad Getz, Francois Aguet, Nada Jabado, Olaf Witt, Stefan Pfister, Keith Ligon, Volker Hovestadt, Claudia Kleinman, Henry Long, David Jones, Pratiti Bandopadhayay, Timothy Phoenix
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Diffuse midline gliomas (DMGs) are a universally fatal brain tumor of childhood. While histone mutations are a critical tumor initiating event, they are insufficient to drive gliomagenesis. Histone mutations co-occur with somatic alterations in other pathways including TP53, MAPK, and MYC signaling. However, the mechanisms through which these pathways are activated have not been fully elucidated. METHODS We applied an integrative approach using transcriptomics, epigenetics, proteomics, in vitro cancer models, and in vivo mouse models to systematically evaluate how FOXR2 mediates gliomagenesis. RESULTS We have recently found that a subset of DMGs aberrantly express FOXR2, a forkhead transcription factor. FOXR2 is both sufficient to enhance tumor formation, and necessary for FOXR2-expressing DMGs. While FOXR2 indeed enhances MYC protein stability, FOXR2 exerts oncogenesis through MYC-independent functions and specifically hijacks E26-transformation specific (ETS) transcriptional circuits and FOXR2 DNA-binding is highly enriched at ETS motifs. We have performed proteomic and phospho-proteomic analysis of FOXR2-expressing human neural stem cells to identify proteins and phospho-sites that are highly enriched in FOXR2-expressing cells. CONCLUSION Taken together, this study elucidates how FOXR2 interacts with ETS transcription factors to mediate oncogenesis in FOXR2-expressing diffuse midline gliomas.
TRLS-06. A PHASE 1, SAFETY AND DOSE ESCALATION STUDY OF BXQ-350 IN COMBINATION WITH RADIATION IN PEDIATRIC PATIENTS WITH DIFFUSE MIDLINE GLIOMA OR DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Kathleen Dorris, Maryam Fouladi, Trent Hummel, Scott Raskin, Richard Curry III, Joseph Purvis, Michael Gazda, Gilles Tapolsky, Ray Takigiku
Journal: Neuro-Oncology (2023)

Abstract This trial (NCT04771897) is currently enrolling at 3 US sites; as of January 2023, a total of 8 patients have been enrolled. Enrollment of cohort 1 (2.4 mg/kg and 54 Gy) and cohort 2 (3.2 mg/kg and 54 Gy) are completed. Enrollment in the expansion cohort is on-going. To date, no dose-limiting toxicity has been observed and the combination of BXQ-350 plus radiation has been well tolerated. BXQ-350 is a nanovesicle formulation of Saposin C that induces apoptosis of cancer cells and an anti-tumoral immune response by lowering Sphingosine-1-Phosphate and increasing ceramides concentrations. Saposin C is a human protein encoded by the Psap gene and is an allosteric activator of enzymes involved in sphingolipid/ceramide metabolism. The significance of sphingolipid metabolism in brain cancers has been demonstrated and enzymes involved in sphingolipid metabolism are being investigated as novel therapeutic targets for adult and pediatric brain cancers. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in pediatric brain cancer patients (NCT03967093); results showed that it was well-tolerated, a MTD was not established, and the safety profile warranted the investigation of combination studies at the highest dose tested (3.2 mg/kg). Additionally, results from a Phase 1 safety and dose escalation study in adult patients with advanced solid malignancies (NCT02859857) indicated that BXQ-350 was well tolerated and showed single agent activity with evidence of modulating sphingolipid metabolism and favorably influencing the tumor microenvironment. The primary objective of this dose-escalation study is to describe the safety profile and to determine the maximum tolerated dose of BXQ-350 in combination with radiation. BXQ-350 is administered intravenously concurrently with radiation therapy followed by adjuvant BXQ-350 until disease progression. Multiple secondary parameters are included to characterize BXQ-350’s pharmacokinetic parameters and efficacy profile and to investigate potential biomarkers.